Clinical and neuroimaging features of PRRT2-related epilepsy in adult patients

While proline-rich transmembrane protein 2 (PRRT2) variants have been reported in association with self-limited infantile epilepsy (SeLIE), their relevance to adult epilepsy remains largely uncharacterized. Therefore, we investigated the prevalence of PRRT2 variants in an adult epilepsy cohort to broaden their phenotypic spectrum.

In a cohort of adult patients with epilepsy who underwent whole-exome sequencing (WES), individuals harboring PRRT2 variants were identified and selected for further analysis. Amino acid conservation among species, combined with functional verification of mutant proteins, was performed to assess the pathogenicity of novel PRRT2 variants. Furthermore, electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) were conducted in patients carrying PRRT2 variants.

Two novel missense variants (c.643C > A/ p.P215T and c.932G > A/ p.R311Q) were demonstrated to impair protein expression, indicating a likely haploinsufficiency mechanism. Nine cases were identified carrying PRRT2 variants, including the c.649dupC hotspot variant and two missense variants. The age of seizure onset was predominantly during infancy or adolescence, with epilepsy persisting or relapsing into adulthood. Drug-resistant epilepsy was observed in two cases, whereas others were primarily controlled through sodium channel blockers. Unlike previously reported normal interictal EEG findings in PRRT2-related disorders, epileptiform discharges were recorded in the majority of patients. fMRI revealed reduced thalamocortical connectivity, indicating disrupted brain network integration.

This study expands the genotypic and phenotypic spectrum of PRRT2-related disorders, links its variants to epileptiform discharges, and reveals impaired network integration in PRRT2-associated epilepsy.